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Am J Physiol Endocrinol Metab. 2019 Jul 30. doi: 10.1152/ajpendo.00096.2019. [Epub ahead of print]

eNOS Deletion Impairs Mitochondrial Quality Control and Exacerbates Western Diet Induced NASH.

Author information

1
Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri 65212. Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.
2
Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, United States.
3
Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri 65212. Departments of Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri, United States.
4
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, Kansas City VA Medical Center, Kansas City, MO 64128, United States.
5
Biomedical Sciences, University of Missouri, Columbia, Missouri, United States.
6
Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri 65212, USA; Departments of Medicine-Division of Gastroenterology and Hepatology; Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.

Abstract

Dysregulated mitochondrial quality control leads to mitochondrial functional impairments that are central to the development and progression of hepatic steatosis to steatohepatitis (NASH). Here we identify hepatocellular localized endothelial nitric oxide synthase (eNOS) as a novel master regulator of mitochondrial quality control. Mice lacking eNOS were more susceptible to western diet induced hepatic inflammation and fibrosis in conjunction with decreased markers of mitochondrial biogenesis and turnover. The hepatocyte specific influence was verified via Magnetic Activated Cell Sorting (MACS) purified primary hepatocytes and in vitro siRNA induced knock down of eNOS. Hepatic mitochondria from eNOS knockout mice revealed decreased markers of mitochondrial biogenesis (PGC1α, TFAM) and autophagy/mitophagy (BNIP3, LC3), suggesting decreased mitochondrial turnover rate. eNOS knockout in primary hepatocytes exhibited reduced fatty acid oxidation capacity and were unable to mount a normal BNIP3 response to a mitophagic challenge compared with WT mice. Finally, we demonstrate that eNOS is required in primary hepatocytes to induce activation of the stress responsive transcription factor, NRF2. Thus, our data demonstrate that eNOS is an important regulator of hepatic mitochondrial content and function and NASH susceptibility.

KEYWORDS:

NAFLD; endothelial nitric oxide synthase; mitophagy; steatohepatitis

PMID:
31361543
DOI:
10.1152/ajpendo.00096.2019

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